1. Field of the Invention
The present invention involves compositions and methods for enhancing the permeability of a vessel wall and/or cell membranes of individual cells to increase the uptake of a local drug delivery.
2. Description of the Background
Despite the general success of percutaneous transluminal interventions such as balloon angioplasty, high restenosis rates continue to be a problem. Various techniques have been used to prevent restenosis, including the use of lasers, application of heat and the use of intravascular stents. However, many of these techniques are still under investigation with mixed results, while others have generally not been successful. Local drug delivery has the prospect of surpassing such techniques, provided sufficient drug uptake into the tissue can be obtained.
The treatment of cancerous tumors is another example of a treatment that could be improved by local drug delivery. In the treatment of tumors, an objective is to administer the cancer drug so that it localizes as much as possible in the tumor itself. Such drugs are commonly administered systemically through the blood stream. Various means are then utilized for causing the drug to bind to the cancerous tumor. Nevertheless, significant portions of the drug administered still circulate through the blood stream. As a result, non-cancerous tissue may be affected by the drug, causing undesirable side effects such a systemic toxicity.
A conventional way to deliver drugs locally has been to use a balloon catheter. The balloon is made from a permeable or semipermeable material, which permits transport of the drug across the balloon surface as a result of an appropriate driving force. This driving force may be provided by several different means. For example, an electrical potential may be applied to the permeable or semipermeable membrane to drive ionic drugs or non-ionic drugs carried in an ionic solution across the membrane in a process known as iontophoresis. Alternatively, high frequency or ultra high frequency (ultrasonic) sound waves supplied by a transducer may be used to transport drugs across the semipermeable membrane in a process known as phonophoresis or (synonymously) sonophoresis.
According to another concept, a modified catheter balloon design includes a balloon having a pair of spaced inflatable lobes. After the balloon is properly positioned, the balloon lobes are inflated by introducing an inflation medium (e.g., saline solution). Inflation of the balloon lobes causes the lobes to expand so that their outer peripheral portions engage the inner surfaces of the vessel walls. This engagement defines an open space, a drug treatment zone, between the lobes. A desired drug is then delivered to the open space, such that the drug is in direct contact with the vessel wall.
According to yet another concept, a catheter is provided having a double walled balloon. An inner balloon is provided which is constructed from an impermeable material such as polyethylene. An outer balloon having a permeable or semipermeable membrane is generally concentric to the inner balloon and extends completely around the inner balloon. The outer balloon is first filled with drug. The inner balloon is then inflated with a standard inflation medium (e.g., saline solution). As a result of inflation of the inner balloon, sufficient pressure is developed against the wall of the outer balloon (in contact with the vessel wall) to drive the drug in the outer balloon through the wall of the outer balloon and toward the vessel wall.
According to yet another concept, a stent can be used for the local delivery of a drug. Implementation of local drug delivery via stents has been achieved with the use of a polymeric matrix coated on the stent. The polymeric coating is impregnated with a drug for in vivo sustained release of the drug.
These methods of local drug delivery are effective in placing a drug in contact with a vessel wall. However, the application of the drug appears to be only superficial. In other words, the drug does not penetrate deep into the tissues of the vessel wall, which is believed to be necessary for optimum results. To pose the problem more concretely, by way of one example, the etiology of restenosis is believed to be the excessive migration and proliferation of vascular smooth muscle cells from the tunica media and adventatia layers of the vascular wall to the intimal layer. In order to efficaciously inhibit or treat restenosis, an effective concentration of the drug must, accordingly, reach the vessel wall""s outer layers. With the use of balloons and stents, the exposure of the drug is essentially limited to the intimal layer. The permeability of the vessel wall, therefore, needs to be increased for the local delivery to the sub-layers.
In accordance with one aspect of the invention, a stent having a radially expandable tubular body and a coating, the coating including a permeabilizing reagent for increasing the permeability of membrane junctions or cell membranes, is disclosed. In one embodiment, the permeabilizing reagent can be selected from the group consisting of a calcium ion chelator, a surfactant, and a receptor-mediated permeabilizing reagent. Furthermore, the permeabilizing reagent can be selected from the group consisting of iminodiacetic acid, nitriloacetic acid, ethylenediaminomonoacetic acid, ethylenediaminodiacetic acid, ethylenediaminotetraacetic acid, sodium taurodihydrofusidate, sodium salicylate, sodium caprate, sodium glycocholate, cholylsarcosine, isopropyl myristate, partially hydrolyzed triglycerides, fatty-acid sugar derivatives, oleic acid derivatives, histamine, bradykinin and its conformational analogs, tumor necrosis factor alpha, nitroglycerine, sodium nitroprusside, diethylamine sodium, 3-morpholinosydnonimine, S-nitroso-N-acetyl-penicillamine, and vascular endothelial growth factor and combinations thereof.
In an embodiment, the coating can additionally include a P-glycoprotein system blocker. The P-glycoprotein system blocker can be selected from the group consisting of Pluronic P-85(copyright), verapamil, disulfiram and antisense oligonucleotide complementary to a messenger RNA encoding P-glycoprotein and combinations thereof.
The coating, in addition, can include a drug. The drug can be selected from the group consisting of antineoplastic, antimitotic, antiinflammatory, antiplatelet, antiallergic, anticoagulant, antifibrin, antithrombin, antiproliferative, antioxidant, antimigratory, antiextracellular matrix deposition, pro-apoptotic, nitric oxide donor, pro-angiogenic, and pro-arteriogenic substances and combinations thereof. The coating may also include a polymer.
In accordance with an aspect of the invention, a method of forming a coating for a stent is disclosed, including applying a composition including a permeabilizing reagent and a fluid, and essentially removing the fluid from the composition on the stent to form the coating.
In accordance with another aspect, a method of delivering a drug through a membrane junction or a cell membrane is disclosed, including delivering a permeabilizing reagent to a membrane junction or a cell membrane in a concentration sufficient to increase the permeability of the membrane junction or cell membrane, and delivering a drug to the membrane junction or cell membrane, whereby the drug travels through the membrane junction or cell membrane.
In one embodiment, the permeabilizing reagent is delivered by a stent and/or a catheter. Also, the drug can be delivered by a stent and/or a catheter.
The permeabilizing reagent, in addition, can be a solution including a solute selected from the group consisting of glucose, mannose, maltose, dextrose, fructose, sodium chloride, sodium citrate, sodium phosphate, polyethylene glycol, polyvinyl pyrrolidone and amino acids. Furthermore, the permeabilizing reagent can be selected from the group consisting of iminodiacetic acid, nitriloacetic acid, ethylenediaminomonoacetic acid, ethylenediaminodiacetic acid, ethylenediaminotetraacetic acid, sodium taurodihydrofusidate, sodium salicylate, sodium caprate, sodium glycocholate, cholylsarcosine, isopropyl myristate, partially hydrolyzed triglycerides, fatty-acid sugar derivatives, oleic acid derivatives, histamine, bradykinin and its conformational analogs, tumor necrosis factor alpha, nitroglycerine, sodium nitroprusside, diethylamine sodium, 3-morpholinosydnonimine, S-nitroso-N-acetyl-penicillamine, and vascular endothelial growth factor and combinations thereof.
In accordance with an aspect, a composition for treating restenosis is disclosed, including a permeabilizing reagent and a drug, wherein the permeabilizing reagent increases the permeability of membrane junctions or cell membranes of cells for the delivery of a drug to vascular tissues.
In accordance with another aspect, a method of inhibiting restenosis is disclosed, including applying a permeabilizing reagent to endothelial cells and applying a drug to the area where the permeabilizing reagent is applied.
In accordance with yet another aspect of the present invention, a method of local drug delivery is disclosed, including locally applying a permeabilizing reagent to a selected area of a body tissue, and locally applying a drug to the body tissue.